MV-NIS is an attenuated, oncolytic measles virus that is potently active in preclinical myeloma models and whose in vivo spread can be noninvasively monitored using radioiodine imaging. Myeloma patients have remarkably low antimeasles antibody titers, allowing intravenous delivery of MV-NIS to disseminated disease sites. Concomitant cyclophosphamide can be used to suppress the anamnestic antibody response after virus administration, further enhancing the antitumor efficacy of the virus and allowing repeat dosing. In an ongoing phase I clinical trial we administered MV-NIS intravenously to patients with advanced treatment refractory myeloma at doses up to 109 TCID50. MV-NIS has been very well tolerated at the doses tested and radioiodine imaging studies have proved that circulating virus can localize and selectively amplify at sites of myeloma tumor growth. However, to date the highest MV-NIS dose administered to patients was 3 times less than the minimum effective dose determined in myeloma tumor-bearing mice. Because of a recent breakthrough in the MV-NIS manufacturing methodology we are now proposing to assess the safety, tolerability and preliminary efficacy of 10-fold and 100-fold higher doses of MV-NIS than were previously feasible. Additionally, having conducted extensive mouse experiments to show that a clinically approved 4-day cyclophosphamide regimen can efficiently suppress the antimeasles antibody response in measles-susceptible mice, we now propose to combine this treatment with MV-NIS in the clinical trial to suppress the antimeasles immune response, enhancing the intratumoral spread of the virus and preferentially blocking the formation of antimeasles antibodies, providing a basis for repeat virus administration. A third issue is that our mouse data shows that MV-NIS is much more potent when combined with radioiodine (I131) therapy (radiovirotherapy) but dosimetry calculations from the current clinical protocol show that we need to better protect the thyroid gland from the I131 administration (radiovirotherapy). We therefore propose to test a novel thyroid protective regimen in the planned extension of the trial to pave the way for future clinical radiovirotherapy studies. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page